Search

Abstract Background Soluble urokinase plasminogen activator receptor (suPAR) levels have previously been associated with readmission and mortality in acute medical patients in the ED. However, no specific cut-offs for suPAR have been tested in this population. Methods Prospective observational study of consecutively included acute medical patients. Follow-up of mortality and readmission was carried out for 30- and 90 days stratified into baseline suPAR 6 ng/ml. suPAR levels were measured using suPARnostic® Turbilatex assay on a Cobas c501 (Roche Diagnostics Ltd) analyser. Results A total of 1747 acute medical patients in the ED were included. Median age was 70 (IQR: 57–79) and 51.4% were men. Adjusted linear regression analysis showed that suPAR, independently of age, sex and C-reactive protein levels, predicted 30- and 90-day mortality (Odds ratio for doubling in suPAR 1.96 (95% confidence intervals: 1.42–2.70) Among patients with suPAR below 4 ng/ml (N = 804, 46.0%), 8 (1.0%) died within 90-day follow-up, resulting in a negative predictive value of 99.0% and a sensitivity of 94.6%. Altogether 514 (29.4%) patients had suPAR of 4–6 ng/ml, of whom 43 (8.4%) died during 90-day follow-up. Among patients with suPAR above 6 ng/ml (N = 429, 24.6%), 87 patients (20.3%) died within 90-day follow-up, resulting in a positive predictive value of 20.1% and a specificity of 78.7%. Conclusions suPAR cut-offs of below 4, between 4 and 6 and above 6 ng/ml can identify acute medical patients who have low, medium or high risk of 30- and 90-day mortality. The turbidimetric assay provides suPAR results within 30 min that may aid in the decision of discharge or admission of acute medical patients.

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR ([suPAR.sup.Tg]) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of [suPAR.sup.Tg] mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating [suPAR.sup.Tg] monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function., Introduction People with chronic kidney disease (CKD) are disproportionately affected by cardiovascular disease (CVD), with two-thirds of patients having at least one form of CVD, atherosclerosis being the most common [...]

Background: COVID‐19 disease progression is characterized by hyperinflammation and risk stratification may aid in early aggressive treatment and advanced planning. The aim of this study was to assess whether suPAR and other markers measured at hospital admission can predict the severity of COVID‐19. Methods: The primary outcome measure in this international, multi‐centre, prospective, observational study with adult patients hospitalized primarily for COVID‐19 was the association of WHO Clinical Progression Scale (WHO‐CPS) with suPAR, ferritin, CRP, albumin, LDH, eGFR, age, procalcitonin, and interleukin‐6. Admission plasma suPAR levels were determined using the suPARnostic® ELISA and suPARnostic® Turbilatex assays. Results: Seven hundred and sixty‐seven patients, 440 (57.4%) males and 327 (42.6%) females, were included with a median age of 64 years. Log‐suPAR levels significantly correlated with WHO‐CPS score, with each doubling of suPAR increasing the score by one point (p <.001). All the other markers were also correlated with WHO‐CPS score. Admission suPAR levels were significantly lower in survivors (7.10 vs. 9.63, 95% CI 1.47–3.59, p <.001). A linear model (SALGA) including suPAR, serum albumin, serum lactate dehydrogenase, eGFR, and age can best estimate the WHO‐CPS score and survival. Combining all five parameters in the SALGA model can improve the accuracy of discrimination with an AUC of 0.80 (95% CI: 0.759–0.836). Conclusions: suPAR levels significantly correlated with WHO‐CPS score, with each doubling of suPAR increasing the score by one point. The SALGA model may serve as a quick tool for predicting disease severity and survival at admission. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether the association between levels of medication use (including polypharmacy and potentially inappropriate medications [PIMs]) and health outcomes such as readmission and mortality is dependent on baseline soluble urokinase plasminogen activator receptor (suPAR). Methods: This registry‐based cohort study included medical patients admitted to the emergency department at Copenhagen University Hospital Hvidovre, Denmark. Patients were grouped according to their admission suPAR levels: low (0–3 ng/mL), intermediate (3–6 ng/mL), or high (>6 ng/mL). Hyper‐polypharmacy was defined as ≥10 prescribed medications. PIMs were identified based on the EU(7)‐PIM list, and data on admissions and mortality were obtained from national registries. Risk of 90‐day readmission and mortality was assessed by Cox regression analysis adjusted for sex, age and Charlson comorbidity index. Results were reported as hazard ratios within 90 days of index discharge. Results: In total, 26 291 patients (median age 57.3 y; 52.7% female) were included. Risk of 90‐day readmission and mortality increased significantly for patients with higher suPAR or higher number of medications. Among patients with low suPAR, patients with ≥10 prescribed medications had a hazard ratio of 2.41 (95% confidence interval = 2.09–2.78) for 90‐day readmission and 8.46 (95% confidence interval = 2.53–28.28) for 90‐day mortality compared to patients with 0 medications. Patients with high suPAR generally had high risk of readmission and mortality, and the impact of medication use was less pronounced in this group. Similar, but weaker, association patterns were observed between suPAR and PIMs. Conclusion: The association between levels of medication use and health outcomes is dependent on baseline suPAR. [ABSTRACT FROM AUTHOR]

Background: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown. Methods: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers. Results: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, p < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44–8.27) increase in the odds of death, and 4.9 × (95%CI 2.48–9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint. Conclusion: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable. [ABSTRACT FROM AUTHOR]

Diagnosis of acute kidney injury (AKI) based on plasma creatinine often lags behind actual changes in renal function. Here, we investigated early detection of AKI using the plasma soluble urokinase plasminogen activator receptor (suPAR) and neutrophil gelatinase-sssociated lipocalin (NGAL) and observed the impact of early detection on prescribing recommendations for renally-eliminated medications. This study is a secondary analysis of data from the DISABLMENT cohort on acutely admitted older (≥65 years) medical patients (n = 339). Presence of AKI according to kidney disease: improving global outcomes (KDIGO) criteria was identified from inclusion to 48 h after inclusion. Discriminatory power of suPAR and NGAL was determined by receiver-operating characteristic (ROC). Selected medications that are contraindicated in AKI were identified in Renbase®. A total of 33 (9.7%) patients developed AKI. Discriminatory power for suPAR and NGAL was 0.69 and 0.78, respectively, at a cutoff of 4.26 ng/mL and 139.5 ng/mL, respectively. The interaction of suPAR and NGAL yielded a discriminatory power of 0.80, which was significantly higher than for suPAR alone (p = 0.0059). Among patients with AKI, 22 (60.6%) used at least one medication that should be avoided in AKI. Overall, suPAR and NGAL levels were independently associated with incident AKI and their combination yielded excellent discriminatory power for risk determination of AKI. [ABSTRACT FROM AUTHOR]

Context: Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear., Objective: The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes., Design: The International Study of Inflammation in Covid-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients., Setting: Ten hospitals in the United States and Europe., Participants: Adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022., Main Outcome Measures: Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body-mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed., Results: Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI≥35), those with BMI>40 (n=485) had 55% higher odds of the composite outcome (95% CI[1.21 to 1.98]) compared to non-obese individuals (BMI<30, n=2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants., Conclusion: Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Several scores predicting mortality at the emergency department have been developed. However, all with shortcomings either simple and applicable in a clinical setting, with poor performance, or advanced, with high performance, but clinically difficult to implement. This study aimed to explore if machine learning algorithms could predict all-cause short- and long-term mortality based on the routine blood test collected at admission., Methods: We analyzed data from a retrospective cohort study, including patients > 18 years admitted to the Emergency Department (ED) of Copenhagen University Hospital Hvidovre, Denmark between November 2013 and March 2017. The primary outcomes were 3-, 10-, 30-, and 365-day mortality after admission. PyCaret, an automated machine learning library, was used to evaluate the predictive performance of fifteen machine learning algorithms using the area under the receiver operating characteristic curve (AUC)., Results: Data from 48,841 admissions were analyzed, of these 34,190 (70%) were randomly divided into training data, and 14,651 (30%) were in test data. Eight machine learning algorithms achieved very good to excellent results of AUC on test data in a of range 0.85-0.93. In prediction of short-term mortality, lactate dehydrogenase (LDH), leukocyte counts and differentials, Blood urea nitrogen (BUN) and mean corpuscular hemoglobin concentration (MCHC) were the best predictors, whereas prediction of long-term mortality was favored by age, LDH, soluble urokinase plasminogen activator receptor (suPAR), albumin, and blood urea nitrogen (BUN)., Conclusion: The findings suggest that measures of biomarkers taken from one blood sample during admission to the ED can identify patients at high risk of short-and long-term mortality following emergency admissions., (© 2024. The Author(s).)

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Objectives: To determine the value of the soluble urokinase-type plasminogen activator receptor (suPAR) for predicting outcomes in emergency department (ED) patients. Secondary objectives were 1) to measure the predictive value of the usual decision points, 2) to identify patients at low risk for mortality who could be safely discharged from the ED, and 3) to measure the correlation between suPAR and other biomarkers., Material and Methods: Prospective observational cohort study of patients attended in the EDs of participating hospitals. We recorded sociodemographic variables, comorbidity, variables related to the acute episode, prognostic markers commonly used in EDs, and suPAR concentration. Outcome variables were the need for hospital admission during the index episode, ED revisits within 90 days, and 90-day mortality., Results: A total of 990 patients with a median (interquartile range) age of 68 (53-81 years) were studied; 50.8% were men. The median suPAR concentration was 3.8 (2.8-6.0) ng/mL, and 112 patients (11.31%) required admission. At 90 days there were 276 revisits (27.9% of the cohort), and 47 patients (4.74%) had died. Mortality was lower (1%) in patients with suPAR concentrations less than 4 ng/mL (52.5%), and fewer of these patients revisited (24.4%) or required hospitalization (20.6%) than patients with suPAR concentrations higher than 6 ng/mL (mortality, 13.5%; revisits, 39.6%; admissions, 56.3%). A suPAR concentration over 6 ng/mL was associated with 90-day mortality and revisits (adjusted hazard ratios and 95% CIs of 4.61 [1.68-12.67] and 1.59 [1.13-2.10]), respectively. The high suPAR concentration was also associated with hospital admission (odds ratio, 1.62 [0.99-2.62])., Conclusion: A suPAR concentration of less than 4 ng/mL identifies patients at low risk of 90-day mortality and revisits or need for hospitalization, whereas a suPAR concentration higher than 6 ng/mL is associated with higher risk for these outcomes.

Objective: Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear., Research Design and Methods: We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy., Results: Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels., Conclusions: Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation., (© 2022 by the American Diabetes Association.)

Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19., Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints., Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment., Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS., (© 2021 The Author(s). Published by S. Karger AG, Basel.)